This project involves the examination of the acute mechanisms of pathogenesis by the variant SIVsmmPBj isolate. We have been investigating the ability to prevent the disease induced by this virus by treating animals with immunodmodulatory drugs before infection with virus. Immunomodulatory agents used were BB-94, a metalloproteinase inhibitor, and FK-506, an immunosuppressive drug used for transplantation therapy. FK-506 was the initial drug utilized. Treatment of animals with FK-506 did not prevent or delay development of disease when compared with untreated controls. This drug was subsequently used again, with a minimum dose of virus. As with the first efforts, the FK-506 did not prevent or delay disease development. A similar result was observed with the metalloproteinase inhibitor BB-94. These studies suggest that while the immune activation associated with this virus plays a role in the lethal disease, the virus itself is the determining factor and that growth o f the virus outpaces the ability to repress immune activation in these cases.